We examined femora from adult AXB/BXA recombinant inbred (RI) mouse strains to identify skeletal traits that are functionally related and to determine how functional interactions among these traits contribute to genetic variability in whole-bone stiffness, strength, and toughness. Randomization of A/J and C57BL/6J genomic regions resulted in each adult male and female RI strain building mechanically functional femora by assembling unique sets of morphologic and tissue-quality traits. A correlation analysis was conducted using the mean trait values for each RI strain. A third of the 66 correlations examined were significant, indicating that many bone traits covaried or were functionally related. Path analysis revealed important functional interactions among bone slenderness, cortical thickness, and tissue mineral density. The path coefficients describing these functional relations were similar for both sexes. The causal relationship among these three traits suggested that cellular processes during growth simultaneously regulate bone slenderness, cortical thickness, and tissue mineral density so that the combination of traits is sufficiently stiff and strong to satisfy daily loading demands. A disadvantage of these functional interactions was that increases in tissue mineral density also deleteriously affected tissue ductility. Consequently, slender bones with high mineral density may be stiff and strong but they are also brittle. Thus, genetically randomized mouse strains revealed a basic biological paradigm that allows for flexibility in building bones that are functional for daily activities but that creates preferred sets of traits under extreme loading conditions. Genetic or environmental perturbations that alter these functional interactions during growth would be expected to lead to loss of function and suboptimal adult bone quality.
Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. Genome-wide association studies (GWAS) for BMD have identified dozens of associations; yet, the genes responsible for most associations remain elusive. Here, we used a bone co-expression network to predict causal genes at BMD GWAS loci based on the premise that genes underlying a disease are often functionally related and functionally related genes are often co-expressed. By mapping genes implicated by BMD GWAS onto a bone co-expression network, we predicted and inferred the function of causal genes for 30 of 64 GWAS loci. We experimentally confirmed that two of the genes predicted to be causal, SPTBN1 and MARK3, are potentially responsible for the effects of GWAS loci on Chromosomes 2p16.2 and 14q32.32, respectively. This approach provides a roadmap for the dissection of additional BMD GWAS associations. Furthermore, it should be applicable to GWAS data for a wide range of diseases.
Biomechanical properties were assessed from the tibias of 17 adult males 17-46 years of age. Tissue-level mechanical properties varied with bone size. Narrower tibias were comprised of tissue that was more brittle and more prone to accumulating damage compared with tissue from wider tibias.Introduction: A better understanding of the factors contributing to stress fractures is needed to identify new prevention strategies that will reduce fracture incidence. Having a narrow (i.e., more slender) tibia relative to body mass has been shown to be a major predictor of stress fracture risk and fragility in male military recruits and male athletes. The intriguing possibility that slender bones, like those shown in animal models, may be composed of more damageable material has not been considered in the human skeleton. Materials and Methods: Polar moment of inertia, section modulus, and antero-posterior (AP) and mediallateral (ML) widths were determined for tibial diaphyses from 17 male donors 17-46 years of age. A slenderness index was defined as the inverse ratio of the section modulus to tibia length and body weight. Eight prismatic cortical bone samples were generated from each tibia, and tissue-level mechanical properties including modulus, strength, total energy, postyield strain, and tissue damageability were measured by fourpoint bending from monotonic (n ס 4/tibia) and damage accumulation (n ס 4/tibia) test methods. Partial correlation coefficients were determined between each geometrical parameter and each tissue-level mechanical property while taking age into consideration. Results: Significant correlations were observed between tibial morphology and the mechanical properties that characterized tissue brittleness and damageability. Positive correlations were observed between measures of bone size (AP width) and measures of tissue ductility (postyield strain, total energy), and negative correlations were observed between bone size (moment of inertia, section modulus) and tissue modulus. Conclusions:The correlation analysis suggested that bone morphology could be used as a predictor of tissue fragility and stress fracture risk. The average mechanical properties of cortical tissue varied as a function of the overall size of the bone. Therefore, under extreme loading conditions (e.g., military training), variation in bone quality parameters related to damageability may be a contributing factor to the increased risk of stress fracture for individuals with more slender bones.
Structure-function relationships were determined for L 5 vertebral bodies from three inbred mouse strains. Genetic variability in whole bone mechanical properties could be explained by a combination of the traits specifying the amount, distribution, and quality of the cortical and trabecular bone tissue.Introduction: Although phenotypically correlated with fracture, BMD may be disadvantageous to use in genetic and biomechanical analyses because BMD does not distinguish the contributions of the underlying morphological and compositional bone traits. Developing functional relationships between the underlying bone traits and whole bone mechanical properties should further our understanding of the genetics of bone fragility. Materials and Methods: Microarchitecture and composition of L 5 vertebral bodies (n ס 10/strain) from A/J, C57BL/6J, and C3H/HeJ inbred mouse strains were determined using CT with an isotropic voxel size of 16 m
Foot stiffness underlies its mechanical function, and is central to the evolution of human bipedal locomotion. [1][2][3][4][5] The stiff and propulsive human foot has two distinct arches, the longitudinal and transverse. [3][4][5] By contrast, the feet of non-human primates are flat and softer. 6-8 Current understanding of foot stiffness is based on studies that focus solely on the longitudinal arch, [9][10][11][12][13][14] and little is known about the mechanical function of the transverse arch. However, common experience suggests that transverse curvature dominates the stiffness; a drooping dollar bill stiffens significantly upon curling it along the transverse direction, not the longitudinal. We derive a normalized curvature parameter that encapsulates the geometric principle 15 underlying the transverse curvature-induced stiffness. We show that the transverse arch accounts for almost all the difference in stiffness between human and monkey feet (vervet monkeys and pig-tailed macaques) by comparing transverse curvature-based predictions against published data on foot stiffness. 6,7 Using this functional interpretation of the transverse arch, we trace the evolution of hominin feet [16][17][18][19][20] and show that a human-like stiff foot likely predates Homo by ∼ 1.5 million years, and appears in the ∼ 3.4 million year old fossil from Burtele. 19 A distinctly human-like transverse arch is also present in early members of Homo, including Homo naledi, 20 Homo habilis, 16 and Homo erectus. 17 However, the ∼ 3.2 million year old Australopithecus afarensis 18 is estimated to have possessed a transitional foot, softer than humans and stiffer than other extant primates. A foot with human-like stiffness probably evolved around the same time as other lower limb adaptations for regular bipedality, 3,18,21,22 and well before the emergence of Homo, the longitudinal arch, and other adaptations for endurance running. 2 *
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